Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase

ABSTRACT

Substituted 2-acylaminopyridine compounds and pharmaceutically acceptable salts which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders.

This application is a 371 of PCT/US 95/16158 filed Dec. 8, 1995.

BACKGROUND OF THE INVENTION

This application is directed to inhibitors of nitric oxide synthase, andin particular 2-acylamino-pyridines.

Nitric Oxide in Biology

The emergence of nitric oxide (NO), a reactive, inorganic radical gas asa molecule contributing to important physiological and pathologicalprocesses is one of the major biological revelations of recent times.This molecule is produced under a variety of physiological andpathological conditions by cells mediating vital biological functions.Examples include endothelial cells lining the blood vessels; nitricoxide derived from these cells relaxes smooth muscle and regulates bloodpressure and has significant effects on the function of circulatingblood cells such as platelets and neutrophils as well as on smoothmuscle, both of the blood vessels and also of other organs such as theairways. In the brain and elsewhere nitric oxide serves as aneurotransmitter in non-adrenergic non-cholinergic neurons. In theseinstances nitric oxide appears to be produced in small amounts on anintermittent basis in response to various endogenous molecular signals.In the immune system nitric oxide can be synthesized in much largeramounts on a protracted basis. Its production is induced by exogenous orendogenous inflammatory stimuli, notably endotoxin and cytokineselaborated by cells of the host defense system in response to infectiousand inflammatory stimuli. This induced production results in prolongednitric oxide release which contributes both to host defense processessuch as the killing of bacteria and viruses as well as pathologyassociated with acute and chronic inflammation in a wide variety ofdiseases. The discovery that nitric oxide production is mediated by aunique series of three closely related enzymes, named nitric oxidesynthases, which utilize the amino acid arginine and molecular oxygen asco-substrates has provided an understanding of the biochemistry of thismolecule and provides distinct pharmacological targets for theinhibition of the synthesis of this mediator, which should providesignificant beneficial effects in a wide variety of diseases.

Nitric Oxide Synthases

Nitric oxide and L-citrulline are formed from L-arginine via thedioxygenase activity of specific nitric oxide synthases (NOSs) inmammalian cells. In this reaction, L-arginine, O₂ and NADPH areco-substrates while FMN, FAD and tetrahydrobiopterin are co-factors.NOSs fall into two distinct classes, constitutive NOS (cNOS) andinducible NOS (iNOS) . Two constitutive NOSs have been identified. Theyare:

(i) a constitutive, Ca⁺⁺ /calmodulin dependent enzyme, located in theendothelium (ecNOS or NOS 3), that releases NO in response to receptoror physical stimulation,

(ii) a constitutive, Ca⁺⁺ /calmodulin dependent enzyme, located in thebrain (ncNOS or NOS 1) and elsewhere, that releases NO in response toreceptor or physical stimulation,

The third isoform identified is inducible NOS (iNOS or NOS 2):

(iii) a Ca⁺⁺ independent enzyme which is induced after activation ofvascular smooth muscle, macrophages, endothelial cells, and a largenumber of other cells by endotoxin and cytokines. Once expressed, thisinducible NO synthase produces NO in relatively large amounts for longperiods of time.

Spectral studies of both the mouse macrophage iNOS and rat brain ncNOShave shown that these enzymes (which has been classified as P-450-likeenzymes from their CO-difference spectra) contain a heme moiety. Thestructural similarity between NOS and the P-450-flavoprotein complexsuggests that the NOS reaction mechanism may be similar to P-450hydroxylation and/or peroxidation. This indicates that NOS belongs to aclass of flavohemeproteins which contain both heme and flavin bindingregions within a single protein in contrast to the multiprotein NADPHoxidase or Cytochrome P-450/NADPH Cyt c reductase complexes.

Distinct Functions of NO Produced by Different Nitric Oxide Synthases

The NO released by the constitutive enzymes (NOS 1 and NOS 3) acts as anautocoid mediating a number of physiological responses. Two distinctcDNAs accounting for the activity of NOS 1 and NOS 3 in man have beencloned, one for NOS 1 (Nakane et al., FEBS Letters, 316, 175-182, 1993)which is present in the brain and a number of peripheral tissues, theother for an enzyme present in endothelium (NOS 3) (Marsden et al., FEBSLetters, 307, 287-293, 1992). This latter enzyme is critical forproduction of NO to maintain vasorelaxation. A second class of enzyme,iNOS or NOS 2, has been cloned from human liver (Geller et aL, PNAS, 90,3491-5, 1993), and identified in more than a dozen other cells andtissues, including smooth muscle cells, chondrocytes, the kidney andairways. As with its counterpart from the murine macrophage, this enzymeis induced upon exposure to cytokines such as gamma interferon (IFN-γ),interleukin- 1β (IL-1β), tumor necrosis factor (TNF-α) and LPS(lipopolysaccharide). Once induced, iNOS expression continues over aprolonged period of time. The enzyme does not require exogenouscalmodulin for activity.

Endothelium derived relaxation factor (EDRF) has been shown to beproduced by NOS 3 (Moncada et al., Pharmacol. Reviews, 43, 109-142,1991). Studies with substrate analog inhibitors of NOS have shown a rolefor NO in regulating blood pressure in animals and blood flow in man, afunction attributed to NOS 3. NO has also been shown to be an effectorof the cytotoxic effects of activated macrophages (Nathan, FASEB J., 6,3051-64, 1992) for fighting tumour cells and invading microorganisms(Wright et al., Card. Res., 26,48-57, 1992 and Moncada et al.,Pharmacological Review, 43, 109-142, 1991). It also appears that theadverse effects of excess NO production, in particular pathologicalvasodilation and tissue damage, may result largely from the effects ofNO synthesized by the NOS 2.

NO generated by NOS 2 has been implicated in the pathogenesis ofinflammatory diseases. In experimental animals hypotension induced byLPS or TNF-α can be reversed by NOS inhibitors and reinitiated byL-arginine (Kilbourn et al., PNAS, 87, 3629-32, 1990). Conditions whichlead to cytokine-induced hypotension include septic shock, hemodialysis(Beasley and Brenner, Kidney Int., 42, Suppl., 38, S96-S100, 1992) andIL-2 therapy in cancer patients (Hibbs et al., J. Clin. Invest., 89,867-77, 1992). NOS 2 is implicated in these responses, and thus thepossibility exists that a NOS inhibitor would be effective inameliorating cytokine-induced hypotension. Recent studies in animalmodels have suggested a role for NO in the pathogenesis of inflammationand pain and NOS inhibitors have been shown to have beneficial effectson some aspects of the inflammation and tissue changes seen in models ofinflammatory bowel disease, (Miller et al., J. Pharmacol. Exp. Ther.,264, 11-16, 1990) and cerebral ischemia and arthritis (Ialenti et al.,Br. J. Pharmacol., 110, 701-6, 1993; Stevanovic-Racic et al., Arth. &Rheum., 37, 1062-9, 1994). Moreover transgenic mice deficient in NOS 1show diminished cerebral ischemia (Huang et al., Science, 265, 1883-5,1994).

Further conditions where there is an advantage in inhibiting NOproduction from L-arginine include therapy with cytokines such as TNF,IL-1 and IL-2 or therapy with cytokine-inducing agents, for example 5,6-dimethylxanthenone acetic acid, and as an adjuvant to short termimmunosuppression in transplant therapy. In addition, compounds whichinhibit NO synthesis may be of use in reducing the NO concentration inpatients suffering from inflammatory conditions in which an excess of NOcontributes to the pathophysiology of the condition, for example adultrespiratory distress syndrome (ARDS) and myocarditis.

There is also evidence that an NO synthase enzyme may be involved in thedegeneration of cartilage which takes place in autoimmune and/orinflammatory conditions such as arthritis, rheumatoid arthritis, chronicbowel disease and systemic lupus erythematosis (SLE). It is also thoughtthat an NO synthase enzyme may be involved in insulin- dependentdiabetes mellitus. Therefore, a yet further aspect of the presentinvention provides cyclic amidine derivatives or salts thereof in themanufacture of a medicament for use in cytokine or cytokine-inducingtherapy, as an adjuvant to short term immunosuppression in transplanttherapy, for the treatment of patients suffering from inflammatoryconditions in which an excess of NO contributes to the pathophysiologyof the condition.

SUMMARY OF THE INVENTION

The invention disclosed herein encompasses compounds of Formula (I)##STR1## and pharmaceutically acceptable salts thereof which have beenfound to be useful in the treatment of nitric oxide synthase-mediateddiseases and disorders, including neurodegenerative disorders, disordersof gastrointestinal motility and inflammation. These diseases anddisorders include hypotension, septic shock, toxic shock syndrome,hemodialysis, IL-2 therapy such as in cancer patients, cachexia,immunosuppression such as in transplant therapy, autoimmune and/orinflammatory indications including sunburn, eczema or psoriasis andrespiratory conditions such as bronchitis, asthma, oxidant-induced lunginjury and acute respiratory distress (ARDS), glomerulonephritis,inflammatory sequelae of viral infections, myocarditis, heart failure,atherosclerosis, arthritis, rheumatoid arthritis, chronic orinflammatory bowel disease, ulcerative colitis, Crohn's disease,systemic lupus erythematosis (SLE), ocular conditions such as ocularhypertension, retinitis and uveitis, type 1 diabetes, insulin-dependentdiabetes mellitus and cystic fibrosis. Compounds of Formula I are alsouseful in the treatment of hypoxia, hyperbaric oxygen convulsions andtoxicity, dementia, Sydenham's chorea, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis, mulitple sclerosis, Korsakoff'sdisease, imbecility related to cerebral vessel disorder, NO mediatedcerebral trauma and related sequelae, ischemic brain edema, sleepingdisorders, schizophrenia, depression, pre-menstrual syndrome (PMS),anxiety, drug addiction, pain, migraine, immune complex disease, asimmunosupressive agents, acute allograft rejection, infections caused byinvasive microorganisms which produce NO, radiocontrast induced renalfailure and for preventing or reversing tolerance to opiates anddiazepines.

DETAILED DESCRIPTION OF THE INVENTION

The invention disclosed herein encompasses compounds of Formula (I)##STR2## or a pharmaceutically acceptable salt thereof wherein: R₁, R₂,R₃ and R4 are each independently selected from the group consisting of

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) carboxyl,

(e) aminocarbonyl,

(f) cyano,

(g) nitro,

(h) halo, where halo is selected from fluoro, chloro, bromo, and iodo,

(i) trifluoromethyl,

(j) C₁₋₁₂ alkyl,

(k) C₂₋₁₂ alkenyl,

(l) C₂₋₁₂ alkynyl,

(m) C₁₋₁₂ alkoxy,

(n) C₁₋₁₂ alkylcarbonyl,

(o) C₁₋₁₂ alkoxycarbonyl,

(p) C₁₋₁₂ alkylaminocarbonyl,

(q) mono- and di-C₁₋₁₂ alkylamino,

(r) C₁₋₁₂ alkylthio,

(s) aryl, where aryl is selected from phenyl and naphthyl,

(t) aryloxy, where aryl is selected from phenyl and naphthyl,

(u) arylthio, where aryl is selected from phenyl and naphthyl,

(v) arylC₁₋₆ alkyl, where aryl is selected from phenyl and naphthyl,

(w) cycloalkyl ,wherein the cycloalkyl is a 5- to 10-membered monocyclicring which optionally contains 1 or 2 heteroatoms selected from S, O,and N,

(x) heteroaryl, wherein heteroaryl is selected from the group consistingof:

(1) pyridyl,

(2) pyrrolyl,

(3) furanyl,

(4) thienyl,

(5) isothiazolyl,

(6) imidazolyl,

(7) benzimidazolyl,

(8) tetrazolyl,

(9) pyrazinyl,

(10) pyrimidyl,

(11) quinolyl,

(12) isoquinolyl,

(13) benzofuranyl,

(14) isobenzofuryl,

(15) benzothienyl,

(16) pyrazolyl,

(17) pyrazinyl

(18) indolyl,

(19) isoindolyl,

(20) purinyl,

(21) carbazolyl,

(22) isoxazolyl,

(23) thiazolyl,

(24) triazolyl

(25) oxazolyl,

(26) oxadiazolyl,

(27) thiadiazolyl

(28) benzthiazolyl, and

(29) benzoxazolyl,

(y) heteroarylC₁₋₆ alkyl, where heteroaryl is defined above in item (x),

each of (j) to (y) being optionally mono- or di- substituted, thesubstituents being independently selected from

(1) hydroxy,

(2) C₁₋₆ alkyl,

(3) C₁₋₆ alkoxy,

(4) amino,

(5) mono- and di-C₁₋₆ alkylamino,

(6) carboxyl,

(7) C₁₋₆ alkylthio,

(8) C₁₋₆ alkyl-S(O)_(k) --, where k is 1 or 2,

(9) C₁₋₆ alkoxycarbonyl,

(10) halo selected from fluoro, chloro, bromo, and iodo,

(11) oxo,

(12) amidino,

(13) guanidino,

R₁ and R₂, or R₂ and R₃ or R₃ and R₄ including the optional substituentspresent thereon may be joined together to form a 5- to 10-memberedsaturated or unsaturated ring containing 0, 1 or 2 heteroatoms whichtogether with the atoms to which R₁ and R₂, or R₂ and R₃ or R₃ and R₄are attached there is formed a bicyclic ring according to Formulae(IIa-IIc), the heteroatoms being selected from the group consisting ofO, S and N, ##STR3## R₅ is selected from the group consisting of (a)amino-C(═S)--,

(b) C₁₋₁₂ alkylcarbonyl,

(c) C₂₋₁₂ alkenylcarbonyl,

(d) C₂₋₁₂ alkynylcarbonyl,

(e) C₅₋₁₀ cycloalkylcarbonyl,

(f) arylcarbonyl, wherein the aryl group is selected from phenyl andnaphthyl,

(g) heteroarylcarbonyl, wherein heteroaryl is selected from the groupconsisting of:

(1) pyridyl,

(2) pyrrolyl,

(3) furanyl,

(4) thienyl,

(5) isothiazolyl,

(6) imidazolyl,

(7) benzimidazolyl,

(8) tetrazolyl,

(9) pyrazinyl,

(10) pyrimidyl,

(11) quinolyl,

(12) isoquinolyl,

(13) benzofuranyl,

(14) isobenzofuryl,

(15) benzothienyl,

(16) pyrazolyl,

(17) pyrazinyl

(18) indolyl,

(19) isoindolyl,

(20) purinyl,

(21) carbazolyl,

(22) isoxazolyl,

(23) thiazolyl,

(24) triazolyl

(25) oxazolyl,

(26) oxadiazolyl,

(27) thiadiazolyl

(28) benzthiazolyl, and

(29) benzoxazolyl,

(h) C₁₋₁₂ alkoxycarbonyl,

(i) aryloxycarbonyl, wherein the aryl group is selected from phenyl andnaphthyl,

(j) heteroaryloxycarbonyl, wherein the heteroaryl group is defined asabove in item (g),

(k) arylC₁₋₆ alkoxycarbonyl, wherein the aryl group is phenyl andnaphthyl,

(l) heteroarylC₁₋₆ alkoxycarbonyl, wherein the heteroaryl group isdefined as above in item (g),

(m) C₁₋₁₂ alkylaminocarbonyl,

(n) C₁₋₁₂ alkylaminosulfonyl,

(o) arylaminocarbonyl, wherein the aryl group is selected from phenyland naphthyl,

(p) arylaminosulfonyl, wherein the aryl group is selected from phenyland naphthyl,

(q) heteroarylaminocarbonyl, wherein the heteroaryl group is defined asabove in item (g),

(r) heteroarylaminosulfonyl, wherein the heteroaryl group is definedabove in item (g),

(s) C₁₋₁₂ alkylamino-C(═S)--,

(t) C₂₋₁₂ alkenylamino-C(═S)--,

(u) arylamino-C(═S)--, wherein the aryl group is selected from phenyland naphthyl,

(v) arylC₁₋₆ alkylamino-C(═S)--, wherein the aryl group is selected fromphenyl and naphthyl,

(w) heteroarylamino-C(═S)--, wherein the heteroaryl group is definedabove in item (g),

(x) heteroarylC₁₋₆ alkylamino-C(═S)--, wherein the heteroaryl group isdefined above in item (g),

(y) cycloC₅₋₁₀ alkylamino-C(═S)--,

(z) aryl-C--(═O)--NH--C(═O)--, wherein the aryl group is selected fromphenyl and naphthyl,

(aa) heteroaryl-C(═O)--NH--C(═O)--, wherein the heteroaryl group isdefined above in item (g),

(ab) R₆ R₇ N--SO₂ --NH--C(═O)--, wherein R₆ and R₇ are independentlyselected from the group consisting of

(1) hydrogen,

(2) C₁₋₆ alkyl,

(3) aryl, wherein the aryl group is selected from phenyl and naphthyl,

(4) heteroaryl, wherein the aryl group is selected from the grouppyridyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, and triazolyl,

(5) R₆ and R₇ may be joined together to form a 5- to 10-memberedmonocylic ring containing 0, 1 or 2 heteroatoms, the heteroatoms beingselected from the group of S, O, and N,

each of (b) to (ab) being optionally mono- or di- substituted, thesubstituents being independently selected from

(1) hydroxy,

(2) C₁₋₆ alkyl,

(3) C₁₋₆ alkoxy,

(4) amino,

(5) mono- and di-C₁₋₆ alkylamino,

(6) carboxyl,

(7) C₁₋₆ alkylthio,

(8) C₁₋₆ alkyl-S(O)_(k) --, where k is 1 or 2,

(9) C₁₋₆ alkoxycarbonyl,

(10) halo selected from fluoro, chloro, bromo, and iodo,

(11) oxo,

(12) amidino,

(13) guanidino

Within this embodiment there is the genus of compounds wherein

R₁, R₂, R₃ and R₄ are each independently selected from the groupconsisting of

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) fluoro, chloro, bromo, and iodo,

(f) trifluoromethyl,

(g) C₁₋₆ alkyl,

(h) C₁₋₆ alkoxy,

(i) C1-6alkylthio,

(j) C₁₋₆ alkylcarbonyl,

(k) mono- and di-C₁₋₆ alkylammo,

(1) aryl, where aryl is phenyl and naphthyl,

(m) aryloxy, where aryl is phenyl and naphthyl,

(n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-memberedmonocyclic ring which optionally contains 1 or 2 heteroatoms selectedfrom S, O, and N,

(o) heteroaryl, wherein heteroaryl is selected from the group consistingof:

(1) pyridyl,

(2) furanyl,

(3) thienyl,

(4) pyrazinyl,

(5) pyrimidyl,

(6) thiazolyl, and

(7) triazolyl,

each of (g) to (o) being optionally mono- or di- substituted, thesubstituents being independently selected from

(1) hydroxy,

(2) C₁₋₄ alkyl,

(3) C₁₋₃ alkoxy,

(4) amino,

(5) mono- and di-C₋₆ alkylamino,

(6) carboxyl,

(7) C₁₋₃ alkylthio,

(8) C₁₋₃ alkyl-S(O)_(k) --, where k is 1 or 2,

(9) C₁₋₄ alkoxycarbonyl,

(10) halo selected from fluoro, chloro, bromo, and iodo,

(11) oxo,

(12) amidino,

R₁ and R₂, or R₂ and R₃ or R₃ and R₄ including the optional substituentspresent thereon may be joined together to form a 5-, 6- or 7-memberedsaturated monocyclic ring containing 0, 1 or 2 heteroatoms whichtogether with the atoms to which R₁ and R₂, or R₂ and R₃ or R₃ and R₄are attached there is formed a bicyclic ring according to Formulae(IIa-IIc), the heteroatoms being selected from the group consisting ofO, S and N, ##STR4## R₅ is selected from the group consisting of (a)amino-C(═S)--,

(b) C₁₋₆ alkylcarbonyl,

(c) aroyl, wherein the aroyl group is benzoyl,

(d) C₁₋₆ alkylamino-C(═S)--,

(e) C₂₋₆ alkenylamino-C(═S)--,

(f) arylarnino-C(═S)--, wherein the aryl group is phenyl and naphthyl

(g) arylC1-6alkylamino-C(═S)', wherein the aryl group is phenyl andnaphthyl,

(h) cycloC₅₋₇ alkylamino-C(═S)--,

(i) aroylaminocarbonyl, wherein the aroyl group is benzoyl andnaphthoyl,

(j) R₆ R₇ N--SO₂ --NH--C(═O)--, wherein R₆ and R₇ are independentlyselected from the group consisting of

(1) hydrogen,

(2) C₁₋₆ alkyl

(3) aryl, wherein the aryl group is selected from phenyl,

(4) R₆ and R₇ may be joined together to form a 5 5-, 6- or 7-memberedring containing 0 to 2 heteroatoms, the heteroatoms being elected fromthe group of oxygen, sulfur and nitrogen,

each of (b) to (j) being optionally mono- or di- substituted, thesubstituents being independently selected from

(1) hydroxy,

(2) C₁₋₄ alkyl,

(3) C₁₋₃ alkoxy,

(4) amino,

(5) mono- and di-C₁₋₆ alkylamino,

(6) carboxyl,

(7) C₁₋₃ alkylthio,

(8) C₁₋₃ alkyl-S(O)_(k) --, where k is 1 or 2,

(9) C₁₋₄ alkoxycarbonyl,

(10) halo selected from fluoro, chloro, bromo, and iodo,

(11) oxo,

(12) amidino.

Within this genus there is a class of compounds wherein R₁, R₂, R₃ andR₄ are each independently selected from the group consisting of

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) fluoro, chloro or bromo,

(f) trifluoromethyl,

(g) C₁₋₄ aLkyl,

(h) C₁₋₄ alkoxy,

(i) C₁₋₄ alkylthio,

(j) mono- and di-C₁₋₄ alkylamino,

R₁ and R₂, or R₂ and R₃ or R₃ and R₄ including the optional substituentspresent thereon may be joined together to form a 5, 6 or 7-memberedunsaturated monocyclic ring containing 0, 1 or 2 heteroatoms whichtogether with the atoms to which R₁ and R₂, or R₂ and R₃ or R₃ and R₄are attached there is formed a bicyclic ring according to Formulae(IIa-IIc), the heteroatoms being selected from the group consisting ofO, S and N, ##STR5## R₅ is selected from the group consisting of (a)amino-C(═S)--,

(b) C₁₋₄ alkylamino-C(═S)--,

(c) C₂₋₄ alkenylamino-C(═S)--,

(d) arylamino-C(═S)--, wherein the aryl group is phenyl and naphthyl,

(e) arylC1-4alkylamino-C(═S)--, wherein the aryl group is phenyl,

(f) R₆ R₇ N--SO₂ --NH--C(═O)--, wherein R₆ and R₇ are independentlyselected from the group consisting of

(1) hydrogen,

(2) C₁₋₄ alkyl

(3) aryl, wherein the aryl group is selected from phenyl,

each of (b) to (f) being optionally mono- or di- substituted, thesubstituents being independently selected from

(1) hydroxy,

(2) C₁₋₄ alkyl,

(3) C₁₋₃ alkoxy,

(4) amino,

(5) mono- and di-C₁ -6alkylamino,

(6) carboxyl,

(7) C₁₋₃ alkylthio,

(8) halo selected from fluoro, chloro, and bromo.

Within this class are compounds wherein the rings of Formulae IIa, IIband IIc are selected from the group consisting of ##STR6##

Within the above genus of compounds of Formulae IIa, IIb and IIc whereR₁, R₂, R₃ or R₄ is not explicitly joined into a ring, then

R₁, R₂, R₃ and R₄ are each independently selected from the groupconsisting of

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) fluoro, chloro or bromo,

(f) trifluoromethyl,

(g) C₁₋₄ alkyl,

(h) C₁₋₄ alkoxy,

(i) C₁₋₄ alkylthio,

(j) mono- and di-C₁₋₄ alkylamino,

R₅ is selected from the group consisting of

(a) amino-C(═S)--,

(b) C₁₋₄ alkylamino-C(═S)--,

(c) C₂₋₄ alkenylarnino-C(═S)--,

(d) arylamino-C(═S)--, wherein the aryl group is phenyl and naphthyl,

(e) arylC1-4alkylamino-C(═S)--, wherein the aryl group is phenyl,

(f) R₆ R₇ N--SO₂ --NH--C(═O)--, wherein R₆ and R₇ are independentlyselected from the group consisting of

(1) hydrogen,

(2) C₁₋₄ alkyl

(3) aryl, wherein the aryl group is selected from phenyl,

each of (b) to (f) being optionally mono- or di- substituted, thesubstituents being independently selected from

(1) hydroxy,

(2) C₁₋₄ alkyl,

(3) C₁₋₃ alkoxy,

(4) amino,

(5) mono- and di-C₁₋₆ alkylamino,

(6) carboxyl,

(7) C₁₋₃ alkylthio,

(8) halo selected from fluoro, chloro, and bromo.

Illustrating the invention are the compounds provided in Table 1.

For purposes of this specification alkyl is defmed to include linear,branched, and cyclic structures, with C₁₋₆ alkyl including methyl,ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C₁₋₆alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atomsof a straight, branched, or cyclic configuration. Examples of loweralkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, cyclohexyloxy, and the like. Likewise, C₁₋₆ aLkylthio isintended to include alkylthio groups of from 1 to 6 carbon atoms of astraight, branched or cyclic configuration. Examples of lower alkylthiogroups include methylthio, propylthio, isopropylthio, cycloheptylthio,etc. By way of illustration, the propylthio group signifies --SCH₂ CH₂CH₃.

Heteroaryl includes but is not limited to, pyridyl, pyrrolyl, furanyl,thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl,pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuranyl,isobenzofuryl, benzothienyl, pyrazolyl, pyridazinyl, indolyl,isoindolyl, purinyl, carboxazolyl, isoxazolyl, thiazolyl, triazolyl,oxazolyl, oxadiazolyl, thiadiazolyl, benzthiazolyl and benzoxazolyl.

As outlined in the summary of the invention, the compounds of theinstant invention are useful for in the treatment of a number of NOSimplicated diseases. The implication of these diseases is welldocumented in the literature. For example, with regard to psoriasis, seeRuzicka et al., J. Invest. Derm., 103: 397 (1994) or Kolb-Bachofen etal., Lancet, 344: 139 (1994) or Bull, et al., J. Invest. Derm.,103:435(1994); with regard to uveitis, see Mandia et al., InvestOpthalmol., 35: 3673-89 (1994); with regard to type 1 diabetes, seeEisieik & Leijersfam, Diabetes & Metabolism, 20: 116-22 (1994) orKroncke et al., BBR C, 175: 752-8 (1991) or Welsh et al., Endocrinol.,129: 3167-73 (1991); with regard to septic shock, see Petros et al.,Lancet, 338: 1557-8 (1991),Thiemermann & Vane, Eur. J. Phannacol., 211:172-82 (1992), or Evans et al., Infec. Imm., 60: 4133-9 (1992), orSchilling et al., Intensive Care Med., 19: 227-231 (1993); with regardsto pain, see Moore et al, Brit. J. Pharmacol., 102: 198-202 (1991), orMoore et al, Brit. J. Pharmacol., 108: 296-97 (1992) or Meller et al.,Europ. J. Phannacol., 214: 93-6 (1992) or Lee et al., NeuroReport, 3:841-4 (1992); with regard to migraine, see Olesen et aL, TIPS, 15:149-153 (1994); with regard to rheumatoid arthritis, see Kaurs &Halliwell, FEBS Letters, 350: 9-12 (1994); with regard toosteoarthritis, see Stadler et aL, J. Immunol., 147: 3915-20 (1991);with regard to inflammatory bowel disease, see Miller et al., Lancet,34: 465-66 (1993) or Miller et al., J. Pharmacol. Exp. Ther., 264: 11-16(1993); with regard to asthma, see Hamid et al., Lancet, 342: 1510-13(1993) or Kharitonov, et aL, Lancet, 343: 133-5 (1994); with regard toImmune complex diseases, see Mulligan et al., Br. J. Pharmacol., 107:1159-62 (1992); with regard to multiple sclerosis, see Koprowski et al.,PNAS, 90: 3024-7 (1993); with regard to ischemic brain edema, seeNagafuji et al., Neurosci., 147: 159-62 (1992) or Buisson et al., Br. J.Pharmacol., 106: 766-67 (1992) or Trifiletti et al., Europ. J.Phannacol., 218: 197-8 (1992); with regard to toxic shock syndrome, seeZembowicz & Vane, PNAS, 89: 2051-55 (1992); with regard to heartfailure, see Winlaw et al., Lancet, 344: 373-4 (1994); with regard toulcerative colitis, see Boughton-Smith et aL, Lancet 342: 338-40 (1993);and with regard to atherosclerosis, see White et al., PNAS, 91: 1044-8(1994); with regard to glomerulonephritis, see Muhl et al., Br. J.Pharmcol, 112: 1-8 (1994); with regard to paget's disease andosteoporosis, see Lowick et al., J. Clin. Invest., 93: 1465-72 (1994);with regard to inflammatory sequelae of viral infections, see Koprowskiet al., PNAS, 90: 3024-7 (1993); with regard to retinitis, see Goureauet al., BBRC, 186: 854-9 (1992); with regard to oxidant induced lunginjury, see Berisha et al., PNAS, 91: 744-9 (1994); with regard toeczema, see Ruzica, et al., J. Invest. Derm., 103:395(1994); with regardto acute allograft rejection, see Devlin, J. et al., Transplantation,58:592-595 (1994); with regard to infection caused by invasivemicroorganisms which produce NO, see Chen, Y and Rosazza, J. P. N.,Biochem. Biophys. Res. Comm., 203:1251-1258(1994), and with regard toradiocontrast induced renal failure, see Schwaartz, et al., Am. J.Physiol, 267:F374-9 (1994).

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethyl-cellulose, methylcellulose, hydroxy-propylmethy-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy beans, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

Dosage levels of the order of from about 0.01 mg to about 140 mg/kg ofbody weight per day are useful in the treatment of the above-indicatedconditions, or alternatively about 0.5 mg to about 7 g per patient perday. For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day, or alternatively about 0.5 mg to about 3.5 g perpatient per day, preferably 2.5 mg to 1 g per patient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

Synthesis of 2-Aminopyridines

Several methods for preparing the compounds of this invention areillustrated in the following schemes and examples. Some of the compoundsare known in the literature and are commercially available. Severalreviews for the preparation of 2-aminopyridine derivatives have appeared(M. T. Leffler in Organic Reactions, Vol. 1, R. Adams, ed., J. Wiley andSons, NY, 1942, Ch. 4, pp. 91-104; A. S. Tomcufcik and L. N., Starker inThe Chemistry of Heterocyclic Compounds, Pyridine and Its Derivatives,Part 3, E. Klingsberg, ed.; Interscience, NY, 1962, Ch. IX, pp. 1-177;E. F. V. Scriven in Comprehensive Heterocyclic Chemistry, Vol. 2, Part2A, A. J. Boulton and A. McKillop, eds., Pergamon Press, NY, 1984, Ch.2.05, pp. 165-314).

In one method illustrated Scheme 1, these compounds are prepared by theChitchibabin reaction involving the reaction of a substituted pyridinederivative with sodium amide or sodium amide in the presence of asubstituted amine to yield a 2-aminopyridine derivative. Thismethodology is amenable to a broad range of substitutents. The pyridineand substituted amine starting materials are commercially available orthey can be prepared by the methods known to those skilled in the art.##STR7##

As shown in Scheme 2, the Hofmann rearrangement of apyridyl-2-carboxamide in the presence of a hypohalite will give a2-aminopyridine. Similarly, a Curtius rearrangement of apyridyl-2-hydrazide will also give the desired derivative. Similarly, aLossen rearrangement of a pyridyl-2-hydroxamic acid will also afford2-aminopyridine. Similarly, treatment of apyridyl-2-hydroxamate-O-sulfonic acid with acid gives 2-aminopyridine(Neber-type rearrangement). Picolinic acid starting materials arecommercially available or they can be prepared by the methods known tothose skilled in the art. see E. P. Oliveto in The Chemistry ofHeterocyclic Compounds, Pyridine and Its Derivatives, Part 3, E.Klingsberg, ed.; Interscience, NY, 1962, Ch. X, pp. 179-346.! ##STR8##

As outlined in Scheme 3, 2-halopyridines can be reacted with ammonia orsubstituted amines in the presence of copper (II) sulfate to form the2-aminopyridine derivative. The preparation of a variety of2-halopyridine derivatives has been reviewed (see H. E. Mertel in TheChemistry of Heterocyclic Compounds, Pyridine and Its Derivatives, Part2 E. Klingsberg, ed.; Interscience, NY, 1962, Ch. VI, pp. 299-419). Arecent publication describes new methodology for the preparation ofhighly finctionalized 2-halopyridine derivatives (see P. Rocca et al.,J. Org. Chem. 1993, 58, 7832-7838).

Displacement of a 2-trifluoromethyl group with sodium amide in liquidammonia also gives 2-aminopyridine. ##STR9##

More recent methodology for the synthesis of 2-aminopyridine derivativeshas recently been described (K. Wachi and A. Terada, Chem. Pharm. Bull.Jap., 1980, 28, 465-472) and is outlined in Scheme 4. Pyridine-N-oxidescan react with the imidoyl chloride of 1,3-benzoxazine to giveN-(2-pyridyl)-1,3-benzoxazines. Subsequent treatment with strong acidaffords the 2-aminopyridine. ##STR10##

Methodology for the acylation of the 2-aminopyridines is outlined inScheme 5. Briefly, an appropriately substituted 2-aminopyridine A iseither a) reacted with an acid chloride derivative yield the amide B; orb) reacted with an isocyanate derivative to yield the urea C; or c)reacted first with thiophosgene followed by treatment with an amine toalso yield the thiourea D; or d) reacted with an isothiocyanatederivative to yield the thiourea D. Other methodologies for theacylation of nitrogen have been described (See for example, AdvancedOrganic Chemistry, Thrid Ed, Jerry March, ed., John Wiley & Sons, pp 370to 380) and can also be applied. ##STR11## The N'-(aminosulfonyl)-ureasC were prepared following methodology described by Karady et al. inHeterocycles, 1979, 12, 815-818 and illustrated in Scheme 6. Thus, theappropriately substituted 2-aminopyridine A is reacted withchlorosulfonyl isocyanate in the presence of an organic base, such astriethylamine and diisopropylethylamine, to afford the intermediatethiatriazene B. Treatment of B with the appropriate R₆ R₇ NH amine, in asuitable solvent, such as acetonitrile, yields the desiredN'-(aminosulfonyl)-urea C. ##STR12##

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

all operations were carried out at room or ambient temperature, that is,at a temperature in the range 18-25° C.; evaporation of solvent wascarried out using a rotary evaporator under reduced pressure (600-4000pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60° C.; thecourse of reactions was followed by thin layer chromatography (TLC) andreaction times are given for illustration only; melting points areuncorrected and `d` indicates decomposition; the melting points givenare those obtained for the materials prepared as described; polymorphismmay result in isolation of materials with different melting points insome preparations; the structure and purity of all final products wereassured by at least one of the following techniques: TLC, massspectrometry, nuclear magnetic resonance (NMR) spectrometry ormicroanalytical data; yields are given for illustration only; whengiven, NMR data is in the form of delta (δ) values for major diagnosticprotons, given in parts per million (ppm) relative to tetramethylsilane(TMS) as internal standard, determined at 400 MHz or 500 MHz using theindicated solvent; conventional abbreviations used for signal shape are:s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: inaddition "Ar" signifies an aromatic signal; chemical symbols have theirusual meanings; the following abbreviations have also been used v(volume), w (weight), b.p. (boiling point), m.p. (melting point), L(liter(s)), niL (milliliters), g (gram(s)), mg (milligrams(s)), mol(moles), mmol (millimoles), eq (equivalent(s)).

EXAMPLE 1 ##STR13## N-(2-(4-Methylpyridyl))-N'-(4-methylphenyl)-urea

A mixture of 2-amino-4-methylpyridine (108 mg; 1 mM) and 4-methylphenylisocyanate (133 mg; 1 mM) in 5 mL of ether was stirred overnight at roomtemperature. The resulting white solid was filtered and washed twicewith small amounts of ether. Drying the solid in vacuo resulted in 49 mgof the desired title compound.

¹ H NMR (CDCl₃): 8.07 (d; J=5.5Hz; 1H); 7.47 (d; J=8.5 Hz; 2H); 7.12 (d;J=8.5 Hz; 2H); 6.75 (d; J=5.5 Hz; 1H); 6.72(s; 1H); 2.31(s; 3H); 2.32(s;3H).

EXAMPLE 2 ##STR14## N-(2-(4-Methylpyridyl))-thiourea

To a stirred mixture of 2-amino-4-methylpyridine (505 mg) in chloroform(5 mL) and saturated sodium bicarbonate (5 mL) at 0° C. was addedthiophosgene (1 eq., 0.36 mL). The reaction was gradually warmed to roomtemperature and stirred for 30 minutes. The two layers were separatedand the aqueous layer successively extracted with chloroform (3×10 mL).The combined organic phases were successively washed with water (10 niL)and saturated salt solution (10 mL) and concentrated by rotoevaporation.The residue was dissolved in saturated methanolic ammonia (10 mL). Afterstirring at room temperature for 3 hr, the reaction mixture wasconcentrated by rotoevaporation. The crude product was purified by flashcolumn chromatography on silica gel eluted with 30% ethyl acetate inhexanes to yield the desired product (0.14 gm).

¹ H NMR (CDCl₃): 8.08, 8.05 (d, 1H), 7.9 (br s, 1H), 6.80, 6.68 (d, 1H),2.3(s,3H).

EXAMPLE 3 ##STR15## N-(2-(4,6-dimethylpyridyl))-thiourea

The title compound was synthesized according to the procedure in Example2 by employing 2-amino-4,6-dimethylpyridine instead of2-amino-4-methylpyridine.

¹ H NMR (500 MHz, DMSO) : δ 10.70 (brs, 1H), 10.33 (brs, 1H), 8.76 (brs,1H), 6.75 (s, 1H), 6.70 (s, 1H), 2.32 (s, 3H), 2.19 (s, 3H).

¹³ C NMR (DMSO) 181.04, 154.86, 153.66, 150.16, 118.71, 109.99, 23.89,21.09 ppm.

EXAMPLE 4 ##STR16## N-(2-(5-trifluoromethylpyridyl))-N'-allyl-thiourea

2-Amino-5-trifluoromethylpyridine (3.0 gm, 18.5 mmol) was added to allylisothiocyanate (1.20 mL, 18.5 mmol) and heated to 100° C. The reactionmixture turned solid after about 1 hour. The reaction was stopped after6 hours and cooled. The solid was washed with hexanes, filtered anddried under vacuum to yield the title compound (3.29 g).

¹ H NMR (500 MHz, CDCl₃): δ 11.65 (brs, 1H), 9.88 (brs, 1H), 8.48 (s,1H), 7.85 (dd, 1H), 7.1 l(d, 1H), 6.02 (m, 1H), 5.35-5.24 (m, 2H), 4.43(m, 2H).

¹³ C NMR (CDCl₃) 179.61, 155.31, 143.61, 135.66, 116.88, 112.13, 47.97ppm.

EXAMPLE 5 ##STR17## N-(2-(4,6-dimethylpyridyl))-N'-allyl-thiourea

The title compound was synthesized according to the procedure in Example4 by employing 2-amino-4,6-dimethylpyridine instead of2-amino-5-trifluoromethylpyridine.

¹ H NMR (500 MHz, CDCl₃): δ 12.16 (brs, 1H), 9.07 (brs, 1H), 6.62 (s,1H), 6.48 (s, 1H), 6.04 (m, 1H), 5.36-5.20 (m, 2H), 4.39 (m, 2H), 2.42(s, 3H), 2.26 (s, 3H).

¹³ C NMR (CDCl₃): 179.65, 154.55, 153.05, 150.29, 133.28, 118.64,109.15,47.79, 23.63, 21.05 ppm .

EXAMPLE 6 ##STR18## N-(2-(4-Methylpyridyl))-N'-isopropyl-thiourea

A mixture of 2-amino-4-methylpyridine (108 mg; 1 mmol) and isopropylisothiocyanate (101 mg; 1 mmol) in benzene (5 mL) was heated to refluxfor 1.5 days during which period all the solvent evaporated. The residuewas purified by column chromatography on silica gel using 25% ethylacetate in hexane to give the desired product as creamy solid.

¹ H NMR (D₆ -DMSO)): 8.07 (d; J=5.5 Hz; 1H); 6.95 (s; 1H); 6.86 (d;J=5.5Hz; 1H); 4.4 (m; 1H); 2.26 (s; 3H); 1.24 (d; 6H)

EXAMPLE 7 ##STR19## N-(2-(4-Methylpyridyl))-N'-ethyl-thiourea.

The title compound was synthesized according to the procedure in Example6 by employing ethyl isothiocyanate instead of isopropyl isothiocyanate.

¹ H NMR (D₆ -DMSO)): 8.07 (d; J=5.5 Hz; 1H); 6.95 (s; 1H); 6.87 (d;J=5.5 Hz; 1H); 3.6 (q; 2H); 4.4 (m; 1H); 2.25 (s; 3H); 1.18 (t; 3H).

EXAMPLE 8 ##STR20## N-(2-(4-Methylpyridyl))-N'-phenyl-thiourea

A mixture of 2-amino-4-methylpyridine (108 mg, 1 mmol) and phenylisothiocyanate (135 mg, 1 mmol) in ether (5 mL) was stirred at roomtemperature for 1 day. A solid separated and the supernatant wasdecanted. The solid was rinsed thoroughly with small amounts of ether(2x). The resulting white solid was dried in vacuo to give the desiredproduct (52 mg).

¹ H NMR (D₆ -DMSO)): 8.17 (d; J=5 Hz; 1H); 7.18-7.7 (br m, 5H); 7.06 (s;1H); 6.96(d; J=5 Hz; 1H); 2.3(s; 3H).

EXAMPLE 9 ##STR21## N-(2-Pyridyl)-N'-(4-bromophenyl)-thiourea

The title compound was synthesized according to the procedure in Example8 by employing 4-bromophenyl isothiocyanate instead of phenylisothiocyanate and 2-aminopyridine instead of 4-methyl-2-aminopyridine.

¹ H NMR (CDCl₃): 8.33 (d; 1H); 7.85 (t; 1H); 7.7 (d; 2H); 7.57 (d; 2H);7.23 (d; 1H); 7.16 (t; 1H).

EXAMPLE 10 ##STR22## N-(2-(4-Methylpyridyl))-N'-(1-naphthyl)-thiourea

The title compound was synthesized according to the procedure in Example8 by employing 1-naphthyl isothiocyanate instead of phenylisothiocyanate.

¹ H NMR (D₆ -DMSO)): 8.18 (d; J=5 Hz; 1H); 7.52-8.02 (br m, 7H); 7.13(s;1H); 6.99 (d; J=5 Hz; 1H); 2.32 (s; 3H).

EXAMPLE 11 ##STR23##N-(2-(4-Methylpyridyl))-N'-(3-fluorophenyl)-thiourea

The title compound was synthesized according to the procedure in Example8 by employing 3-fluorophenyl isothiocyanate instead of phenylisothiocyanate.

¹ H NMR (D₆ -DMSO)): 8.2 (d; J=5.5 Hz; 1H); 7.0-7.92 (br m, 5H); 7.06(s; 1H); 6.98 (d; J=5.5 Hz; 1H); 2.3(s; 3H).

EXAMPLE 12 ##STR24## N-(² -(⁴ -Methylpyridyl)-N'-benzyl-thiourea.

A mixture of ² -amino-4-methylpyridine (108 mg, 1 mmol), benzylisothiocyanate (149 mg; 1 mmol) in toluene (2 mL) was heated to refluxfor 3 days during which period the solvent evaporated. The residue waspurified by column chromatography on silica gel using 25% of ethylacetate in hexane to give the title compound (109 mg).

¹ H NMR (D₆ -DMSO)): 8.02 (d; J=5.5 Hz; 1H); 7.2-7.36 (br m, 5H); 6.98(s; 1H); 6.87 (d; J=5.5 Hz; 1H); 4.9 (d; 2H); 2.26 (s; 3H)

EXAMPLE 13 ##STR25##N-(2-(4-Methylpyridyl))-N'-(3,3,,5-trimethylcyclohexyl)-thiourea.

Mixture of 2-amino-4-methylpyridine (108 mg, 1 mmol) and 3,3,5-trimethylcyclohexyl isothiocyanate (187 mg, mmol) in 2 mL of toluene was heatedto reflux for 2 days. The solvent was removed and the residue waspurified by column chromatography on silica gel using 25% ethyl acetatein hexane to provide the title compound (136 mg).

¹ H NMR (D₆ -DMSO)): 8.06 (d; J=5 Hz; 1H); 6.94(s, 1H); 6.86 d; J=5 Hz;1H); 4.34 (m; 1H); 2.26 (s; 3H); 0.72-2.1 (br m, 7H); 0.88 (d; 3H); 0.92(s, 3H), 0.93 (s; 3H).

EXAMPLE 14 ##STR26## N-(2-(4-Methylpyridyl))-N'-benzoyl-urea

Benzoyl isocyanate (147 mg, 1 mmol) was added dropwise to a suspensionof 2-amino-4-methylpyridine (108 mg, 1 mmol) in ether (10 mL) at roomtemperature. A precipitate formed instantaneously. After stirring 4hours at room temperature, solid was filtered and washed with ethertwice. The resulting white solid was dried in vacuo to give titlecompound (105 mg).

¹ H NMR (D₆ -DMSO)): 8.18 (d; J=5 Hz; 1H); 7.5-8.2 (br m, 5H); 7.13 (s;1H); 6.98 (d; J=5 Hz; 1H); 2.34 (s; 3H).

EXAMPLE 15 ##STR27##N-(2-(4-Methylpyridyl))-N'-(((S)-4-amino-4-carboxy)-n-butyl)-thioureaStep A:N-(2-(4-Methylpyridyl))-N'-(((S)-4-t-butoxycarbonylamino-4-t-butoxycarbonyl)-n-butyl)-thiourea.

To a stirred mixture of 0.105 g (0.36 mmol) of N.sup.α(t-butoxycarbonyl)-(S)-ornithine t-butyl ester (Tet. Lett. 1991, 32,875-878) in chloroform (2 mL) and CaCO₃ (0.11 g, 1.1 mmol) in water (2.5mL) was added thiophosgene (42 uL, 0.55 mmol) at 0° C. The reaction wasallowed to warm to room temperature and stirred for 45 min. The solutionwas diluted with methylene chloride and the layers were separated. Theorganic layer was washed with saturated salt solution, dried andconcentrated to about 2 mL. This solution was transferred to a vial and2-amino-4-methylpyridine (44 mg, 0.41 mmol ), triethylamine (70 uL, 0.5mmol) and 4-dimethylaminopyridine (trace) were added. The vial wastighly capped and heated in a 40° C. bath over a weekend. The solutionwas cooled to room temperature and partitioned between water andmethylene chloride. The methylene chloride layer was washed withsaturated sodium bicarbonate, saturated salt solution, dried andconcentrated by rotoevaporation. The residue was purified by preparativethin layer chromatography eluted with ethyl acetate to yield desiredproduct (94 mg, 64% yield).

¹ H NMR (CDCl₃) δ: 1.42 (s, 9H), 1.44 (s, 9H), 1.5-2.0 (m, 4H), 2.30 (s,3H), 3.72 (m, 2H), 4.21 (m, 1H), 5.08 (d, 1H, J=8 Hz), 6.45 (s, 1H),6.76 (d, 1H, J=4 Hz), 8.05 (d, 1H, J=4 Hz), 8.1 (br s, 1H).

Step B:N-(2-(4-Methylpyridyl))-N'-(((S)-4-amino-4-carboxy)-n-butyl)-thiourea.

Hydrogen chloride gas was passed through ethyl acetate (2 mL) at 0° C.until it was saturated. This solution (2 mL) was added toN-(2-(4-Methylpyridyl))-N'-(((S)-4-t-butoxycarbonylamino-4-t-butoxycarbonyl)butyl)-thiourea(from step A, 94 mg, 0.21 mmol) and the mixture was stirred for 20 h. Awhite solid was formed. The mixture was diluted with ether, the solidwas filtered, washed with fresh ether and dried to yield the titlecompound as a hygroscopic solid (72 mg, 95% yield).

¹ H NMR (CD₃ OD) 6: 1.75-2.1 (m, 4H), 2.56 (s, 3H), 3.69 (t, 2H, J=6Hz), 4.04 (t, 1H, J=6 Hz), 7.30 (s, 1H), 7.35 (d, 1H, J=6 Hz), 8.22 (d,1H, J=6 Hz).

Mass Spectrum m/e=283 (M+1).

EXAMPLE 16 ##STR28## N-(2-Pyridyl)-N'-(diethylaminosulfonyl)-urea

This example was prepared according to the general procedure describedby Karady et al. in Heterocycles, 1979, 12, 815-818. To a solution of2-aminopyridine (5.0 g, 0.053 mol) in acetonitrile (17.5 mL) cooled to0° C. was added chlorosulfonylisocyanate (4.5 mL) while maintaining thetemperature between -5 and +5° C. A very thick precipitate formed. Thecooling bath was removed, and the reaction mixture was allowed to warmto room temperature. The mixture was re-cooled to 0° C., anddiisopropylethylamine (8 mL, 0.046 mol) was added dropwise with stirringwhile maintaining the internal temperature between -5 and +5° C. Anadditional 0.85 mL of diisopropylethylamine was added, and the mixturewas allowed to warm to room temperature and stirred overnight. The solidthat formed was filtered, washed with cold acetonitrile, and dried invacuo; yield 6.0 g. To a mixture of this1,2,4,6-thiatriazene-1,1-dioxide (2.0 g, 0.010 mol) in acetonitrile (60mL) was added diethylamine (0.97 mL, 9.38 mmol). The reaction mixturewas stirred overnight at room temperature and evaporated. The resultingsolid was triturated with methanol, filtered, washed with diethyl ether,and dried in vacuo; yield 1.6 g (55%).

¹ H NMR (CD₃ OD) δ: 1.20 (t, 3H), 3.42 (q, 2H), 7.06 (dd, 1H), 7.22 (brm, 1H), 7.76 (m, 1H), 8.23 (m, 1H).

Mass Spectrum m/e=273 (M+1).

EXAMPLE 17 ##STR29##N-(2-(3-Methylpyridyl)-N'-(diethylaminosulfonyl)-urea

This example was prepared in a manner analogous to that described forthe preparation of Example 16, but substituting 2-amino-3-picoline inplace of 2-aminopyridine.

¹ H NMR (CD₃ OD) δ: 1.20 (t, 3H), 2.29 (s, 3H), 3.43 (q, 2H), 7.04 (dd,1H), 7.65 (d, 1H), 8.12 (d, 1H).

Mass Spectrum m/e=287 (M+1).

EXAMPLE 18 ##STR30##N-(2-(4-Methylpyridyl)-N'-(diethylaminosulfonyl)-urea

This example was prepared in a manner analogous to that described forthe preparation of Example 16, but substituting 2-amino-4-picoline inplace of 2-aminopyridine.

¹ H NMR (CD₃ OD) δ: 1.20 (t, 3H), 2.33 (s, 3H), 3.42 (q, 2H), 6.91 (d,1H), 7.02 (br s, 1H), 8.09 (d, 1H).

Mass Spectrum m/e=287 (M+1).

EXAMPLE 19 ##STR31##N-(2-(5-Methylpyridyl)-N'-(diethvlaminosulfonyl)-urea

This example was prepared in a manner analogous to that described forthe preparation of Example 16, but substituting 2-amino-5-picoline inplace of 2-aminopyridine.

¹ H NMR (CD₃ OD) δ: 1.20 (t, 3H), 2.29 (s, 3H), 3.42 (q, 2H), 7.12 (brs, 1H), 7.60 (dd, 1H), 8.08 (d, 1H).

Mass Spectrum m/e=287 (M+1).

EXAMPLE 20 ##STR32##N-(2-(4-Methylpyridyl)-N'-(diethylaminosulfonyl)-N'-methyl-urea

To a solution of N-(2-(4-methylpyridyl)-N'-(diethylaminosulfonyl)-urea(100 mg, 0.349 mmol) in 4:1 benzene-methanol (2 mL) was added(trimethylsilyl)diazomethane (2.0 M solution in hexanes, 0.175 mL, 0.35mmol). The reaction mixture was stirred for one hour at room temperatureand then evaporated. Pure title compound was obtained afterchromatography on silica gel (25% acetone/hexane as eluant); yield 85 mg(81%).

¹ H NMR (CDl₃ OD) δ: 1.20 (t, 3H), 2.38 (s, 3H), 3.20 (s, 3H), 3.40 (q,2H), 6.97 (d, 1H), 7.88 (s, 1H), 8.09 (d, 1H).

Mass Spectrum m/e=301 (M+1).

EXAMPLE 21 ##STR33## Oxalamide, N-(4-methyl-2-pyridyl), methyl ester

To a solution of 2-amino-4-picoline (500 mg, 4.62 mmol) in methylenechloride (15 mL) cooled in an ice-bath were added triethylamine (1.4 mL,0.010 mol) followed by a solution of methyl oxalyl chloride (0.467 mL,5.08 mmol) in methylene chloride (5 mL) dropwise with stirring. Thereaction mixture was stirred for one hour at ice temperature, dilutedwith methylene chloride, washed with water, saturated sodium bicarbonatesolution, saturated brine solution, dried (Na₂ SO₄), and evaporated.Pure title compound was obtained as a white solid after chromatographyon silica gel (5% acetone/hexane as eluant); yield 195 mg (22%).

¹ H NMR (CD₃ OD) δ: 2.37 (s, 3H), 3.74 (s, 3H), 6.98 (d, 1H), 7.95 (brs, 1H), 8.12 (d, 1H).

Mass Spectrum m/e=195 (M+1).

EXAMPLE 22 ##STR34## Malonamide, N-(4-methyl-2-pyridyl), methyl ester

To a solution of 2-amino-4-picoline (500 mg, 4.62 mmol) intetrahydrofuran (15 mL) cooled in an ice-bath were added triethylamine(0.710 mL, 5.09 mmol) followed methyl malonyl chloride (0.520 mL, 4.85mmol) dropwise with stirring. The cooling bath was removed, and thereaction mixture was stirred overnight at room temperature. The mixturewas partitioned between ethyl acetate and water. The organic layer waswashed with 2N hydrochloric acid, saturated sodium bicarbonate solution,saturated brine solution, dried (Na₂ SO₄), and evaporated. Pure titlecompound was obtained as a white solid after chromatography on silicagel (30% ethyl acetate/hexane as eluant); yield 535 mg (56%).

¹ H NMR (CD₃ OD) δ: 2.39 (s, 3H), 3.32 (s, 2H), 3.93 (s, 3H), 7.07 (d,1H), 7.99 (br s, 1H), 8.19 (d, 1H).

Mass Spectrum m/e=209 (M+1).

Isolation and Purification of Nitric Oxide Synthases

Methods demonstrating the isolation and purification of all threeisoforms of NOS have been published and reviewed in U. Forstermann, J.S. Pollock, W. R. Tracey, M. Nakane in Methods in Enzymology, Vol. 233,L. Packer, ed., Academic Press, NY, 1994, Ch.26, pp. 258-264. Cloned andexpressed NOS has also been demonstrated and reviewed in C. J Lowensteinand S. H. Snyder in Methods in Enzymology, Vol. 233, L. Packer, ed.,Academic Press, NY, 1994, Ch.26, pp. 264-269.

Assay Protocol for NOS activity

Various assays for NOS activity have been reported in the literature andare reviewed in the following: M. E. Murphy and E. Noack in Methods inEnzymology, Vol. 233, L. Packer, ed., Academic Press, NY, 1994, Ch.26,pp. 240-250 and J. M. Hevel and M. A. Marletta in Methods in Enzymology,Vol. 233, L. Packer, ed., Academic Press, NY, 1994, Ch.26, pp. 250-258.Details for the assay protocols to measure NOS activity are as follows:

NOS activity is measured as the formation of L- 2,3,4,5-³ H!Citrullinefrom L- 2,3,4,5-³ H!Arginine. The incubation buffer (100 μL) contained;100 mM TES, pH 7.5, 5 μM FAD, 5 μM FMN, 10 μM BH₄, 0.5 mM NADPH, 0.5 mMDTT, 0.5 mg/mL BSA, 2 mM CaCl2, 10 μg/mL calmodulin (bovine), 1 μML-Arg, 0.2 μCi L- 2,3,4,5-³ H!Arg, and the inhibitor in aqueous DMSO(max. 5 %). The reaction is initiated by addition of enzyme. Incubationsare performed at room temperature for 30 minutes and stopped by theaddition of an equal volume of quenching buffer consisting of 200 mMsodium citrate, pH 2.2, 0.02% sodium azide. Reaction products areseparated by passing through a cation exchange resin and quantitated ascpm by scintillation counting. Percent inhibition is calculated relativeto enzyme incubated without inhibitor according to: % inhibition=100×(cpm L- 2,3,4,5-³ H!Cit with inhibitor/cpm L- 2,3,4,5-³ H!Citwithout inhibitor).

Illustrative of the utility of the compounds of Formula I is the abilityof such compounds to inhibit NO synthase as shown in Table 1 and asmeasured by the assay described above:

                  TABLE 1    ______________________________________    Inhibition of Human Inducible Nitric Oxide Synthase by    2-Acylamino-Pyridines    Example         % inh. @ IC.sub.50    No              50 μM (μM)    ______________________________________    1               54       <50    2               63       <50    3               75       <50    4               86       <10    5               51       <50    6               100      <1    7               100      <10    8               50       ND*    9               55       <50    10              54       ND    11              70       <50    12              76       <50    13              57       <50    14              96       <10    15              85       <10    16              55       <10    17              100      <10    18              92       <1    19              100      <50    20              100      <1    21              100      <1    22              57       >50    ______________________________________     *ND = Not determined.

What is claimed is:
 1. A compound of Formula (I) ##STR35## or apharmaceutically acceptable salt thereof wherein: one of R₁ and R₂, R₂and R₃ or R₃ and R₄ including the optional substituents present thereon,is joined together to form a 5-, 6- or 7-membered saturated monocyclicring containing 0, 1 or 2 heteroatoms which together with the atoms towhich R₁ and R₂, or R₂ and R₃ or R3 and R₄ are attached there is formeda bicyclic ring according to Formulae (IIa-IIc), the heteroatoms beingselected from the group consisting of O, S and N, ##STR36## and whereinthe rings of Formulae IIa, IIb and IIc are selected from the groupconsisting of ##STR37## and the remaining R₁, R₂, R₃ and R₄ groups areeach independently selected from the group consisting of:(a) hydrogen,(b) hydroxy, (c) amino, (d) cyano, (e) halo selected from the groupconsisting of: fluoro, chloro, bromo, and iodo, (f) trifluoromethyl, (g)C₁₋₆ alkyl, (h) C₁₋₆ alkoxy, (i) C₁₋₆ alkylthio, (j) C₁₋₆ alkylcarbonyl,(k) mono- and di-C₁₋₆ alkylamino, (l) aryl, where aryl is phenyl andnaphthyl, (m) aryloxy, where aryl is phenyl and naphthyl, (n)cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclicring which optionally contains 1 or 2 heteroatoms selected from S, O,and N, (o) heteroaryl, wherein heteroaryl is selected from the groupconsisting of:(1) pyridyl, (2) furanyl, (3) thienyl, (4) pyrazinyl, (5)pyrimidyl, (6) thiazolyl, and (7) triazolyl, each of (g) to (o) beingoptionally mono- or di- substituted, the substituents beingindependently selected from:(1) hydroxy, (2) C₁₋₄ alkyl, (3) C1-3alkoxy,(4) amino, (5) mono- and di-C₁₋₆ alkylamino, (6) carboxyl, (7) C₁₋₃alkylthio, (8) C₁₋₃ alkyl-S(O)_(k) --, where k is 1 or 2, (9) C₁₋₄alkoxyearbonyl, (10) halo selected from the group consisting of:fluoro,chloro, bromo, and iodo, (11) oxo and (12) amidino, and R₅ is selectedfrom the group consisting of(a) amino-C(═S)--, (b) C₁₋₆ alkylcarbonyl,(c) aroyl, wherein the aroyl group is benzoyl, (d) C₁₋₆alkylamino-C(═S)--, (e) C₂₋₆ alkenylamino-C(═S)--, (f)arylamino-C(═S)--, wherein the aryl group is phenyl and naphthyl (g)arylC1-6alkylamino-C(═S)--, wherein the aryl group is phenyl andnaphthyl, (h) cycloC₅₋₇ alkylamino-C(═S)--, (i) aroylaminocarbonyl,wherein the aroyl group is benzoyl and naphthoyl, (j) R₆ R₇ N--SO₂--NH--C(═O)--, wherein R₆ and R₇ are independently selected from thegroup consisting of(1) hydrogen, (2) C₁₋₆ alkyl (3) aryl, wherein thearyl group is selected from phenyl, (4) R₆ and R₇ may be joined togetherto form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms,the heteroatoms being elected from the group of oxygen, sulfur andnitrogen, each of (b) to (j) being optionally mono- or di- substituted,the substituents being independently selected from(1) hydroxy, (2) C₁₋₄alkyl, (3) C₁₋₃ alkoxy, (4) amino, (5) mono- and di-C₁₋₆ alkylamino, (6)carboxyl, (7) C₁₋₃ alkylthio, (8) C₁₋₃ alkyl-S(O)_(k) --, where k is 1or 2, (9) C₁₋₄ alkoxycarbonyl, (10) halo selected from the groupconsisting of:fluoro, chloro, bromo, and iodo, (11) oxo, and (12)amidino.
 2. A compound according to claim 1 whereinthe remaining R₁, R₂,R₃ and R₄ groups are each independently selected from the groupconsisting of:(a) hydrogen, (b) hydroxy, (c) amino, (d) cyano, (e)fluoro, chloro or bromo, (f) trifluoromethyl, (g) C₁₋₄ alkyl, (h) C₁₋₄alkoxy, (i) C₁₋₄ alkylthio, (j) mono- and di-C₁₋₄ alkylamino, and R₅ isselected from the group consisting of(a) amino-C(═S)--, (b) C₁₋₄alkylamino-C(═S)--, (c) C₂₋₄ alkenylamino-C(═S)--, (d)arylamino-C(═S)--, wherein the aryl group is phenyl and naphthyl, (e)arylC1-4alkylamino-C(═S)--, wherein the aryl group is phenyl, (f) R₆ R₇N--SO₂ --NH--C(═O)--, wherein R₆ and R₇ are independently selected fromthe group consisting of(1) hydrogen, (2) C₁₋₄ alkyl (3) phenyl, each of(b) to (f) being optionally mono- or di- substituted, the substituentsbeing independently selected from(1) hydroxy, (2) C1 4alkyl, (3) C₁₋₃alkoxy, (4) amino, (5) mono- and di-C₁₋₆ alkylamino, (6) carboxyl, (7)C₁₋₃ alkylthio, and (8) halo selected from the group consistingof:fluoro, chloro and bromo.
 3. A compound according to claim 2whereinR₂ is hydrogen or methyl, R₄ is hydrogen or methyl, R₁ and R₃ areeach independently selected from(a) hydrogen, (b) methyl, ethyl, propylor butyl, (c) chloro, (d) --CN, and (e) --CF₃, R₅ is selected from thegroup consisting of(a) amino-C(═S)--, (b) C₁₋₄ alkylamino-C(═S)--, (c)C₂₋₄ alkenylamino-C(═S)--, (d) arylamino-C(═S)--, wherein the aryl groupis phenyl and naphthyl, (e) arylC1-4alkylamino-C(═S)--, wherein the arylgroup is phenyl, (f) R₆ R₇ N--SO₂ --NH--C(═O)--, wherein R₆ and R₇ areindependently selected from the group consisting of(1) hydrogen, (2)C₁₋₂ alkyl, (3) phenyl, each of (b) to (f) being optionally mono- or di-substituted, the substituents being independently selected from(1)hydroxy, (2) C₁₋₂ alkyl, (3) C₁₋₂ alkoxy, (4) amino, (5) mono- anddi-C₁₋₃ alkylamino, (6) C₁₋₃ alkylthio, (7) halo selected from fluoro,chloro and bromo.
 4. A pharmaceutical composition for treating a nitricoxice synthase mediated disease comprising a pharmaceutical carrier anda non-toxic effective amount of the compound of claim
 1. 5. A method forinhibiting the activity of nitric oxide synthases comprisingadministering to a subject suffering from a nitric oxide synthasemediated disease, a non-toxic therapeutically effective amount of thecompound of claim
 1. 6. A pharmaceutical composition for treating anitric oxide synthase mediated disease comprising a pharmaceuticalcarrier and a non-toxic effective amount of the compound selectedfrom(a) N-(2-(4-Methylpyridyl))-N'-(4-methylphenyl)-urea; (b)N-(2-(4-Methylpyridyl))-thiourea; (c)N-(2-(4,6-dimethylpyridyl))-thiourea; (d)N-(2-(5-trifluoromethylpyridyl))-N'-allyl-thiourea; (e)N-(2-(4,6-dimethylpyridyl))-N'-allyl-thiourea; (f)N-(2-(4-Methylpyridyl))-N'-isopropyl-thiourea; (g)N-(2-(4-Methylpyridyl))-N'-ethyl-thiourea; (h)N-(2-(4-Methylpyridyl))-N'-phenyl-thiourea; (i)N-(2-Pyridyl)-N'-(4-bromophenyl)-thiourea; (j)N-(2-(4-Methylpyridyl))-N'-(1-naphthyl)-thiourea; (k)N-(2-(4-Methylpyridyl))-N'-(3-fluorophenyl)-thiourea; (l)N-(2-(4-Methylpyridyl)-N'-benzyl-thiourea; (m)N-(2-(4-Methylpyridyl))-N'-(3,3,5-trimethylcyclohexyl)-thiourea; (n)N-(2-(4-Methylpyridyl))-N'-benzoyl-urea; and (o)N-(2-(4-Methylpyridyl))-N'-(((S)-4-amino-4-carboxy)-n-butyl)-thiourea;(p) N-(2-Pyridyl)-N'-(1-piperazinylsulfonyl)-urea; (q)N-(2-(3-Methylpyridyl)-N'-(diethylaminosulfonyl)-urea; (r)N-(2-(4-Methylpyridyl)-N'-(diethylaminosulfonyl)-urea; (s)N-(2-(5-Methylpyridyl)-N'-(diethylarninosulfonyl)-urea; (t)N-(2-(4-Methylpyridyl)-N'-(diethylaminosulfonyl)-N'-methyl-urea; (u)Oxalamide, N-(4-methyl-2-pyridyl), methyl ester; and (v) Malonamide,N-(4-methyl-2-pyridyl), methyl ester.